1. Field of the Invention
This invention relates to a new class of 16.alpha.,17.alpha.-acetonide steroids which are 21,21-dihalo substituted. More specifically they are compounds which are 21,21-dihalo-16.alpha., 17.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-diones and the corresponding pregn-4-enes which may have a 6.alpha.-halo substituent, a 9.alpha.-fluoro or chloro substituent, and an 11.beta.-hydroxy substituent or 11.beta.-chloro substituent. The compounds of the invention are useful as topical anti-inflammatories. The invention also relates to a process for making the compounds of this invention which comprises formylating at the 21 position a .DELTA..sup.1,4,9(11) steroid having either one halo substituent or no halo substituents at the 21 position, halogenating, subsequently deformylating, and reacting at the 9(11) double bond to form the compounds of the invention.
2. Prior Art
It is known from U.S. Pat. No. 3,236,866 to Ringold and Edwards that 21,21-difluoro-.DELTA..sup.1 -pregnenes are useful as progestational agents and as such exhibit anti-androgenic, anti-estrogenic and anti-gonadotrophic activity. It is also known from U.S. Pat. No. 3,681,405 patented Aug. 1, 1972 to Laurent et al. that certain 21,21-dichloro steroids have anti-inflammatory activity. The compounds are represented by the formula ##STR2## wherein R.sup.1 is hydrogen or chlorine;
R.sup.2 is hydrogen, fluorine or methyl; PA1 R.sup.3 is hydrogen or methyl; PA1 R.sup.4 is hydrogen or a free or esterified hydroxy group; and PA1 C.sub.1 c.sub.2 represents a single or double bond joining carbon atoms at the 1 and 2 position. PA1 X.sup.1 is hydrogen, fluoro, chloro or bromo; PA1 X.sup.2 is hydroxy or may be chloro when X.sup.1 is chloro; PA1 X.sup.3 and X.sup.4 are independently fluoro, chloro, or bromo; and PA1 the broken line between C-1 and C-2 indicates that the bond between C-1 and C-2 is a single or a double bond. Of the compounds encompassed by the generic formula, the preferred compound is selected from those represented by formula (I) wherein X.sup.3 and X.sup.4 are independently fluoro or chloro and X, X.sup.1, X.sup.2 and the broken line are as previously defined. PA1 X is hydrogen, fluoro, or chloro; PA1 X.sup.1 is hydrogen, fluoro, chloro or bromo; PA1 X.sup.2 is hydroxy or may be chloro when X.sup.1 is chloro; PA1 X.sup.3 and X.sup.4 are independently fluoro, chloro or bromo; and PA1 the broken line between C-1 and C-2 represents a single or a double bond. Thus compounds failling within the scope of the claims include the following compounds which are named as 16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-diones or 16.alpha.,17.alpha.-isopropylidenedioxypregn-4-ene-3,20-diones, with the substituents on the 6.alpha.-,9.alpha.-,11.beta.-,21-positions being named in alphabetical order: PA1 6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden edioxypregna-1,4-diene-3,20-dione; PA1 21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropy lidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-21-chloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-iso propylidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-dibromo-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropy lidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.,21,21-tetrafluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-is opropylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-chloro-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha .-isopropylidenedixoypregna-1,4-diene-3,20-dione; PA1 21-bromo-21-chloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-dibromo-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.-chloro-6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,21-dichloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp ha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-9.alpha.-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,21,21-trichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,21,21-trifluoro-9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-iso propylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,11.beta.,21-trichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha.-iso propylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-9.alpha.,11.beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha .-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,11.beta.,21,21-tetrachloro-16.alpha.,17.alpha.-isopropylidenedioxy pregna-1,4-diene-3,20-dione; PA1 6.alpha.-chloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,21-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-6.alpha.-chloro-21-fluoro-11.beta.-hydroxy- 16.alpha.,17.alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,21,21-trichloro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden edioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.-chloro-9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,21-dichloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp ha.-isopropylidenedioxypregna1,4-diene-3,20-dione; PA1 21-bromo-6.alpha.-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,21,21-trichloro-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.-dichloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp ha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.,21-trichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-6.alpha.,9.alpha.-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.,21,21-tetrachloro-11.beta.-hydroxy-16.alpha.,17.alpha.-is opropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.,11.beta.-trichloro-21,21-difluoro-16.alpha.,17.alpha.-iso propylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.,11.beta.,21-tetrachloro-21-fluoro-16.alpha.,17.alpha.-iso propylidenedioxypregna-1,4-diene-3,20-dione; PA1 21-bromo-6.alpha.,9.alpha.,11.beta.-trichloro-21-fluoro-16.alpha.,17.alpha. -isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 6.alpha.,9.alpha.,11.beta.,21,21-pentachloro-16.alpha.,17.alpha.-isopropyli denedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden edioxypregna-1,4-diene-3,20-dione; PA1 21-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-dichloro-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,11.beta.-dichloro-21,21-difluoro-16.alpha.,17.alpha.-isopropyliden edioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,11.beta.,21-trichloro-21-fluoro-16.alpha.,17.alpha.-isopropylidene dioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.,11.beta.,21,21-tetrachloro-16.alpha.,17.alpha.-isopropylidenedioxy pregna-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha .-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-6.alpha.-chloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxy-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropy lidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha .-isopropylidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropylidenedioxypreg na-1,4-diene-3,20-dione; PA1 9.alpha.-bromo-21-chloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-iso propylidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregna-1,4-diene-3,20-dione; PA1 21,21-dichloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17.alp ha.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 21-bromo-21-chloro-6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,21,21-trifluoro-9.alpha.-chloro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 21-bromo-9.alpha.-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 9.alpha.,21-21-trichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,21,21-trifluoro-9.alpha.,11.beta.-dichloro-16.alpha.,17.alpha.-iso propylidenedioxypregn-4-ene-3,20-dione; PA1 9.alpha.,11.beta.,21-trichloro-6.alpha.-21-difluoro-16.alpha.,17.alpha.-iso propylidenedioxypregn-4-ene-3,20-dione; PA1 21-bromo-9.alpha.,11.beta.-dichloro-6.alpha.,21-difluoro-16.alpha.,17.alpha .-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 9.alpha.,11.beta.-21,21-tetrachloro-16.alpha.,17.alpha.-isopropylidenedioxy pregn-4-ene-3,20-dione; PA1 6.alpha.-chloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,21-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.-chloro-9.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,21-dichloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp ha.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 21-bromo-6.alpha.-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-4-ene-3,20-dione; PA1 6.alpha.,21,21-trichloro-9.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedixoypregn-4-ene-3,20-dione; PA1 6.alpha.,9.alpha.-dichloro-21,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alp ha.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,9.alpha.,21-trichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 21-bromo-6.alpha.,9.alpha.-dichloro-21-fluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,9.alpha.,21,21-tetrachloro-11.beta.-hydroxy-16.alpha.,17.alpha.-is opropylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,9.alpha.,11.beta.-trichloro-21,21-difluoro-16.alpha.,17.alpha.-iso propylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,9.alpha.-11.beta.-21-tetrachloro-21-fluoro-16.alpha.,17.alpha.-iso propylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.-bromo-21-chloro-9.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17 .alpha.-isopropylidenedioxypregna-4-ene-3,20-dione; PA1 6.alpha.,21,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isopropyliden edioxypregn-4-ene-3,20-dione; PA1 21-chloro-6.alpha.,21-difluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregn-4-ene-3,20-dione; PA1 21,21-dichloro-6.alpha.-fluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-isoprop ylidenedioxypregn-4-ene-3,20-dione; PA1 6.alpha.,9.alpha.-21,21-tetrafluoro-11.beta.-hydroxy-16.alpha.,17.alpha.-is opropylidenedioxypregn-4-ene-3,20-dione; PA1 21-chloro-6.alpha.,9.alpha.,21-trifluoro-11.beta.-hydroxy-16.alpha.,17.alph a.-isopropylidenedioxypregn-4-ene-3,20-dione; and other .DELTA..sup.4 steroids corresponding to the .DELTA..sup.1,4 steroids named hereinbefore.
It is further known that 21,21-diiodo, -dibromo, and dichloro steroids are useful as intermediates in preparation of certain steroid compounds. See for example Canadian Pat. No. 769,025; French Pat. No. 1,243,528; U.S. Pat. No. 2,715,621; U.S. Pat. No. 2,752,366; and German Pat. No. DT2225658, the latter patent disclosing the 21,21-diiodo compounds which are useful for the preparation of triamcinalone, fluocinolone, dexamethasone, betamethasone, and paramethasone.